1. Technical Field
This invention relates to a method, apparatus and composition for selectively controlling the temperature of all or a portion of a patient""s body by lowering, maintaining or raising the temperature of a body fluid or tissue to affect the temperature of all or part of the patient""s body, while reducing shivering that typically accompanies such temperature control. More particularly, the invention relates to the application of a method, apparatus and composition of a heat exchange device in combination with an anti-thermoregulatory response mechanism to control the temperature of all of a portion of a patient""s body while reducing shivering, inhibiting vasoconstriction and/or increasing thermal comfort during various therapeutic uses of patient temperature control. The invention also relates to novel compositions that are useful for reducing shivering or inhibiting vasoconstriction.
2. Background
The xe2x80x9cset point temperaturexe2x80x9d is the temperature that the body attempts to maintain through the thermoregulatory responses. Under ordinary circumstances, thermoregulatory responses within the human body which include sweating and vasodilation to enhance heat loss, arterio venous (xe2x80x9cAVxe2x80x9d) shunting and vasoconstriction to enhance retaining heat, and shivering to enhance increased generation of body heat, serve to maintain the body at a near constant set point temperature of about 37xc2x0 C. (98.6xc2x0 F.), often referred to as xe2x80x9cnormothermicxe2x80x9d. However, sometimes the body sets a different set point temperature, for example a patient with a fever has an elevated set point temperature, and these mechanisms can serve to maintain an elevated temperature. In the case of a fever, the set point temperature can be higher than normothermic.
There is a temperature slightly below the set point temperature where the body senses that the body temperature is too low and begins to shiver. This temperature is sometimes referred to as the shivering threshold. As with the set point temperature, the shivering threshold is not an absolute temperature but varies between individuals and within the same individual depending on his or her condition.
As a result of the thermoregulatory responses, any heat lost to the environment is precisely balanced by heat produced within the body. Accordingly, attempts to control the body temperature below the set point temperature often produce shivering in the patient, as this is the main method of generating additional metabolic heat. Shivering can increase heat production by 200-500% and thus presents a serious obstacle when attempts are made to reduce a patient""s body temperature. Even where the attempt is only to control the temperature at some constant temperature, if the patient is shivering this creates such a considerable amount of metabolic heat, and at such wildly varying rates, that precise control of the patient""s temperature is often impossible.
The thermoregulatory responses provide a formidable defense when attempts are made to lower the body temperature below the set point temperature, for example, when one attempts to induce an artificially low body temperature (a condition known as hypothermia) by lowering the normothermic 37xc2x0 C. to a lower temperature state or when one attempts to maintain normothermia by lowering an elevated body temperature to normothermic 37xc2x0 C. Since there are numerous therapeutic reasons for both inducing hypothermia or inducing normothermia in a patient suffering from an elevated temperature, the thermoregulatory responses must be taken into consideration when designing a therapeutic regimen for controlling the temperature of all or a portion of a patient""s body. Indeed, when the patient has a set point temperature that is above normothermic, for example when the patient has a fever, the shivering threshold may actually be above normothermic as well, and thus even an attempt to maintain a patient""s temperature to normothermia may result in shivering. In addition, even when the thermoregulatory responses have been overcome, the body temperature may continue to drop, possibly below the desired threshold. This xe2x80x9covershootingxe2x80x9d phenomenon can lead to complications. Accordingly, any therapeutic regimen for controlling body temperature preferably does so at a carefully monitored and controlled rate.
It has also been found that in rewarming a patient, either after therapeutic hypothermia or a patient suffering from accidental hypothermia, a very gradual and controlled rewarming rate is desirable. The dramatic generation of metabolic heat due to shivering, particularly in addition to heat added by other means, can result in rapid and uncontrolled rewarming. Therefore therapeutic rewarming at a carefully monitored and controlled rate also requires control over shivering.
Hypothermia may be induced to minimize damage to the brain when a patient has suffered a head injury or stroke, or to minimize damage to heart and brain tissue when a patient has undergone cardiac arrest. It may sometimes also be desirable to induce hypothermia during surgery, especially neurosurgery, once again to minimize tissue damage.
Early techniques involved application of cold to the skin surface or cooling the inspired air, alone or in combination with a compound to inhibit the thermoregulatory center such as chlorpromazine (Ripstein, et al., Surgery (35)1:98-103 (1954)). More recently, in situ blood temperature modification using a heat exchange catheter was described in Ginsburg, U.S. Pat. No. 5,486,208 and Ginsburg, WO 98/26831, the disclosures of which are incorporated herein by reference. This in situ procedure lowers the body temperature much faster and maintains the temperature at that lower level more precisely than the cooled skin surface or cooled breathing air methods described above.
There are also drugs which are capable of assisting in lowering body temperature. However, many require toxic doses in order to achieve the desired hypothermic state. Temperature lowering was also allegedly achieved with chlorpromazine, when administered in combination with a refrigeration blanket (Ripstein, et al, supra), and when administered alone (Chai, et al., Br. J. Pharmac. 57:43-49 (1976)). However, in both these instances, temperature variation after the chlorpromazine was administered was achieved by external cooling or exposure alone and without any significant control of the degree or rate of body cooling. More recently, hypothermia was allegedly induced in rats with a combination of a xcexa opioid receptor agonist and a dopamine receptor blocker or agonist (Adler, et al., U.S. Pat. No. 4,758,562).
It has been shown that the xcex12-adrenoreceptor agonists dexmedetomidine and clonidine are able to lower the shivering threshold (Talke, et al., Anesthesiology 87(4):835-841, 1997). In this study, patients at a normal temperature were warmed until sweating then cooled until shivering occurred, as the xcex12-adrenoreceptor agonist was administered. Evaluation of the ability of these agonists and a novel agonist to reduce core temperature were later described in Millan, et al., The Journal of Pharmacology and Experimental Therapeutics 295(3):1192-1205, 2000. However, in both these studies, as with chlorpromazine, temperature variation after the xcex12-adrenoreceptor agonist was administered was achieved with only minor control of the degree or rate of body cooling.
However, in spite of these advances, there continues to be a need to develop a method of safely and temporarily achieving thermoregulatory inhibition such as by inactivating the shivering response or inhibiting vasoconstriction while inducing hypothermia or otherwise reducing the body""s temperature below its set point temperature for an extended period of time, or while gently and slowly raising the body""s temperature from a hypothermic state. A number of therapeutic applications of hypothermia will greatly benefit from an ability to control shivering in an awake patient. The control of shivering and/or vasoconstriction is necessary whenever it is desirable to control the temperature of a patient that is not under general anesthesia (paralyzed and intubated) at a temperature that is below the shivering threshold. For example, in applying hypothermia or therapeutic cooling in at least the following situations, it would be beneficial to be able to control the patient temperature without causing the patient to shiver: treatment of myocardial infarct (xe2x80x9cMIxe2x80x9d); treatment of stroke; treatment of patients undergoing elective Percutaneous Transluminal Coronary Angioplasty (xe2x80x9cPTCAxe2x80x9d), maintaining normothermia in stroke and head trauma; treatment of cardiogenic shock; warming patients post-operatively after they are no longer under general anesthesia but are still below the shivering threshold, subsequent to major surgery especially where the surgery is either very long or involves significant exposure, as where there is a open thorax or abdomen, or where there is a craniotomy; treatment after cardiac arrest; and control of temperature in general where the patient is at a temperature below the shivering threshold but is not under general anesthesia. This invention is directed to such needs.
The present invention pertains to a method for controlling the temperature of all or a portion of a patient""s body to a temperature below its set point temperature, while achieving thermoregulatory response inhibition, comprising the steps of: (a) sensing the temperature of all or a portion of the patient""s body; (b) generating a signal based upon the sensed temperature; (c) controlling the temperature of all or a portion of the patient""s body based upon the signal; and (d) administering a therapeutically effective amount of an anti-thermoregulatory response agent to the patient. The method can further comprise the application of warmth to the skin of the patient.
The present invention also pertains to a method for providing therapeutic temperature control of all or a portion of a patient""s body to a temperature below its set point temperature while reducing shivering in a patient that is being treated for a medical condition, comprising the steps of: (a) sensing the temperature of all or a portion of the patient""s body; (b) generating a signal based upon the sensed temperature; (c) controlling the temperature of all or a portion of the patient""s body based upon said signal by placing a heat exchange device having a heat exchange region into heat exchange proximity with the patient""s body and controlling the temperature of the heat exchange region to control the temperature of all or a portion of the patient""s body; (d) administering an anti-thermoregulatory response mechanism to the patient; and (e) maintaining the temperature of all or a portion of the patient""s body at a therapeutically low temperature for a sufficient time to treat the medical condition.
The therapeutic temperature control may be directed to treatment of various medical conditions including myocardial infarct; of stroke; treatment of patients undergoing elective PTCA, maintaining normothermia in stroke and head trauma; treatment of cardiogenic shock; cardiac arrest; and control of temperature in general where the patient is at a temperature below the shivering threshold but is not under general anesthesia. The therapeutic temperature control may be also be directed to warming patients post-operatively after they are no longer under general anesthesia but are still below the shivering threshold, subsequent to major surgery especially where the surgery is either very long or involves significant exposure, as where there is a open thorax or abdomen, or where there is a craniotomy.
One object of this invention is to utilize the aforementioned method to lower a patient""s body temperature below its set point temperature while reducing shivering.
Yet another object of this invention is to utilize the aforementioned method to raise a patient""s body temperature from an initial temperature below the set point temperature while reducing shivering.
Another object of this invention is to utilize the aforementioned method to raise a patient""s body temperature at a predetermined rate while reducing shivering.
Still another object of this invention is to utilize the aforementioned method to slowly and controllably rewarm a hypothermic patient from a temperature below the set point temperature toward normothermia.
Another object of this invention is to utilize the aforementioned method to maintain a patient""s body temperature at a stable temperature below the set point temperature while reducing shivering.
Another aspect of the invention comprises controlling a patient""s body temperature by placing a heat exchange device having a heat exchange region into the vascular system of the patient and controlling the temperature of the heat exchange region for a sufficient time to affect the temperature of all or a portion of the patient""s body, while administering an anti-thermoregulatory response mechanism to the patient.
Still another aspect of the invention is a method of controlling a patient""s body temperature by administering an anti-thermoregulatory response mechanism to the patient while using a heat exchange device that is a catheter and the heat exchange region comprises a balloon on the catheter, the temperature of the balloon being controlled by the circulation of a heat exchange fluid through the interior of the balloon. The catheter may have a shaft for the circulation of heat exchange fluid, where fluid circulates through the shaft and through the interior of the balloon.
It is another object of the invention to control the temperature of all or a portion of a patient""s body by using a heat exchange device in combination with one or more anti-thermoregulatory response agents selected from the group consisting of: dopamine receptor blockers; dopamine receptor agonists; xcexa opioid receptor agonists; xcexc opioid receptor agonists; opioid agonist-antagonist analgesics; serotonin 5HT1a receptor agonists; xcex12-adrenoreceptor agonists; non-opiod analgesic monoamine uptake inhibitors; and neuropeptides.
Yet another aspect of the invention is a method of controlling the temperature of a patient by using a heat exchange device and administering an anti-thermoregulatory response agent selected from the group consisting of buspirone, ipsapirone, 8-hydroxy-2-(di-n-propylamino)tetralin, flesinoxan, dexmedetomidine, nepofam and neurotensin.
The present invention further comprises a method of controlling a patient""s body temperature below its set point temperature with an internal heat exchange device, while simultaneously inactivating the shivering response of the patient.
One aspect of the invention pertains to a method of controlling the temperature of a patient below the set point temperature comprising the steps of: (a) employing internal in vivo core temperature regulation; and (b) administration of an anti-thermoregulatory response mechanism.
In another aspect of the invention, the step of employing internal in vivo core temperature regulation comprises placing a heat exchange device in the blood vessels of the patient, where the heat exchange device has a heat exchange region which is in contact with the flowing blood of the patient; and controlling the temperature of the heat exchange region for a sufficient time to affect the temperature of the patient, while administering an anti-thermoregulatory response mechanism to the patient.
Yet another aspect of the invention is a kit for controlling the temperature of a patient comprising a heat exchange device and an anti-thermoregulatory response mechanism. The kit may further comprising a set of instructions for use of the heat exchange device and/or administration of the anti-thermoregulatory response mechanism. The kit may also comprise a control system which measures patient body temperature and controls the heat exchange device in response to the body temperature.
Yet another aspect of the invention is to control the temperature of a patient while reducing shivering to treat a medical condition.
Yet another aspect of the invention is to control the temperature of a patient while reducing shivering to treat any condition where a metabolically active organ or portion of the patient""s body is ischemic with temperature below the shivering threshold, including at least: myocardial infarct; stroke; to elective PTCA; to maintain normothermia in stroke and head trauma; to warm patients post-operatively after any major surgery especially where the surgery is either very long or involves significant patient heat loss, as where there is a open thorax or abdomen or a craniotomy; cardiogenic shock; cardiac arrest; or any condition while the patient is awake where it is desirable to control the patient temperature at some temperature below the shivering threshold.
These and other objects of the invention are achieved by the method, apparatus, kit and composition described herein where a patient""s body temperature is lowered, such as by inducing hypothermia, utilizing a heat exchange device in combination with an anti-thermoregulatory response mechanism. Such device can comprise an elongate flexible catheter having a heat exchanger that operates to exchange heat between tissue, blood or other body fluid which flows in or is positioned in heat exchanging proximity thereto.
Further aspects and details of the present invention will become apparent to those of skill in the relevant art upon reading and understanding of the detailed description of preferred embodiments set forth here below. Each of the embodiments disclosed below may be considered individually or in combination with any of the other variations and aspects of the invention.